Hepatic induction potency of hypolipidaemic drugs in the rat following long-term administration: influence of different dosing regimens.
1. The effects of different dosing regimens of three hypolipidaemic, peroxisome-proliferator drugs on hepatic enzymes in the Fischer rat following 26 weeks treatment have been studied. 2. In study 1, with once-daily dosing (dose levels based on comparative antisecretory activity), the liver/body weight ratio and peroxisomal beta-oxidation were significantly increased in the order: ciprofibrate greater than bezafibrate greater than clofibric acid. Glutathione peroxidase activity was decreased to 65% and 77% control after treatment with ciprofibrate and bezafibrate, respectively, but not after treatment with clofibric acid. 3. In study 2, dosing regimens were adjusted to compensate for the different drug pharmacokinetic profiles in rat, with clofibric acid and bezafibrate administered twice daily and ciprofibrate once every 48 h. Liver enlargement and increases in peroxisomal beta-oxidation were similar with all three drugs when compensation for differences in drug clearance was made. Glutathione peroxidase activity was decreased to similar extents by all three compounds. 4. The induction profiles of these hypolipidaemic drugs, largely different with once-daily dosing, were shown to be similar after adjusting the frequency of dosing with respect to drug half-life.
Makowska
J M
JM
University of Surrey, Department of Biochemistry, Guildford, UK.
Bonner
F W
FW
Gibson
G G
GG
D000818:Animals; D001629:Bezafibrate / Q000008:administration & dosage; D002995:Clofibric Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D058607:Fibric Acids; D005979:Glutathione Peroxidase / Q000378:metabolism; D006529:Hepatomegaly / Q000139:chemically induced; D000960:Hypolipidemic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D008099:Liver / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D008297:Male; D008830:Microbodies / Q000187:drug effects / Q000201:enzymology; D051381:Rats
D058607:Fibric Acids; D000960:Hypolipidemic Agents; D002995:Clofibric Acid; D005979:Glutathione Peroxidase; C019304:ciprofibrate; D001629:Bezafibrate